Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:12]\[C:13]1[NH:17][C:16]([CH3:18])=[C:15]([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][CH:25]([C:28]([OH:30])=O)[CH2:24][CH2:23]2)=[O:20])[C:14]=1[CH3:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:65]1[CH2:70][CH2:69][O:68][CH2:67][CH2:66]1>CN(C=O)C>[N:65]1([C:28]([CH:25]2[CH2:24][CH2:23][CH:22]([NH:21][C:19]([C:15]3[C:14]([CH3:31])=[C:13](/[CH:12]=[C:5]4\[C:6](=[O:11])[NH:7][C:8]5[C:4]\4=[CH:3][C:2]([F:1])=[CH:10][CH:9]=5)[NH:17][C:16]=3[CH3:18])=[O:20])[CH2:27][CH2:26]2)=[O:30])[CH2:70][CH2:69][O:68][CH2:67][CH2:66]1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)NC1CCC(C(=O)O)CC1
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)NC1CCC(C(=O)N2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.9 %

Procedure:
To the solution of 4-({5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carbonyl}-amino)-cyclohexanecarboxylic acid in 20 mL of DMF were added HATU (0.161 g, 0.424 mmol), DIEA (0.072 mL, 0.424 mmol) and morpholine (0.0737 g, 0.847 mmol). The reaction mixture was stirred at r.t. overnight. LC-MS was used to determine completion of the reaction. DMF was evaporated under reduced pressure and the residue was precipitated with 5% diethylamine/methanol (5 mL). The precipitate was collected by filtration, washed with methanol and dried in vacuum to give title compound (69 mg, 32.9% yield) as an orange solid. 1H NMR (300 MHz, DMSO-d6): δ=13.66 (s, 1H), 10.87 (s, 1H), 7.71-7.77 (m, 2H), 7.53-7.55 (d, 1H), 6.81-6.92 (m, 2H), 3.95-3.96 (m, 1H), 3.29-3.54 (m, 8H), 2.64-2.67 (m, 1H), 2.39-2.41 (ds, 6H), 1.47-1.88 (m, 8H). LC/MS: 495.1 [M+H]+.
Reaction SMILES: [CH:1]1[C:10]2[C@H:11]3[CH2:16][NH:15][CH2:14][CH2:13][C@H:12]3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][CH:2]=1.Cl[CH2:18][CH2:19][CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH2:29])=[O:22].C([O-])([O-])=O.[K+].[K+]>>[CH:1]1[C:10]2[C@H:11]3[CH2:16][N:15]([CH2:18][CH2:19][CH2:20][C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[NH2:29])=[O:22])[CH2:14][CH2:13][C@H:12]3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][CH:2]=1
Reactant: Nc1ccccc1C(=O)CCCCl
Reactant: c1cc2c3c(c1)[C@H]1CNCC[C@H]1N3CCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Nc1ccccc1C(=O)CCCN1CC[C@@H]2[C@H](C1)c1cccc3c1N2CCC3
Yield: 42.6 %

Procedure:
The title compound (0.080 g, 42%) was prepared by the general method of Example 402 from (7aR,11aS)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline (0.11 g, 0.50 mmol), 4-chloro-2′-aminobutyrophenone (0.20 g, 1.0 mmol), KI (catalytic) and K2CO3 (0.14 g, 1.0 mmol) after chromatographic purification as a white amorphous solid. The 1H NMR was identical to that of Example 404, 4-((7aS,11aR)-5,6,8,9,11,11a-hexahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinolin-10(7aH)-yl)-1-(2-aminophenyl)-1-butanone
Reaction SMILES: [OH:1][CH2:2][C:3]#[C:4][C:5]1[C:6]2[CH2:17][CH2:16][CH2:15][CH2:14][C:7]=2[S:8][C:9]=1[C:10]([O:12][CH3:13])=[O:11].N1C=CN=C1.[CH3:23][C:24]([Si:27](Cl)([CH3:29])[CH3:28])([CH3:26])[CH3:25].CCOC(C)=O>ClCCl>[CH3:13][O:12][C:10]([C:9]1[S:8][C:7]2[CH2:14][CH2:15][CH2:16][CH2:17][C:6]=2[C:5]=1[C:4]#[C:3][CH2:2][O:1][Si:27]([C:24]([CH3:26])([CH3:25])[CH3:23])([CH3:29])[CH3:28])=[O:11]
Reactant: COC(=O)c1sc2c(c1C#CCO)CCCC2
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1sc2c(c1C#CCO[Si](C)(C)C(C)(C)C)CCCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
To a solution of methyl 3-(3-hydroxyprop-1-yn-1-yl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxylate (8.5 g, 34 mmol) in Dichloromethane (DCM) (50 mL) was added 1H-imidazole (5.8 g, 85 mmol) and TBSCl (7.7 g, 50.9 mmol). The mixture was stirred at room temperature for 2 h. The reaction mixture was washed with water, brine, dried over Na2SO4 and concentrated to dryness. The residue was purified by chromatography column on silica gel chromatography eluted with PE:EtOAc=50:1˜20:1 to afford title product (11.9 g, 96% yield). 1HNMR: (400 MHz, CDCl3) δ 0.161 (s, 6H), 0.929 (s, 9H), 1.79-1.85 (m, 4H), 2.60-2.63 (m, 2H), 2.72-2.75 (m, 2H), 3.85 (s, 3H), 4.62 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:31]=[C:32]([F:34])[CH:33]=1)[CH2:5][C@H:6]([NH:22][C:23](=[O:30])[CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])[C@H:7]([OH:21])[CH2:8][NH:9][C:10]1([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][CH3:20])[CH:14]=2)[CH2:12][CH2:11]1.[CH2:35](Cl)[CH2:36]Cl.[CH:39]1[CH:40]=C[C:42]2[N:47](O)N=[N:45][C:43]=2[CH:44]=1>CN(C=O)C>[N:47]12[CH2:36][CH2:35][CH:44]([CH2:39][CH2:40]1)[C@@H:43]([NH:45][C:27](=[O:29])[CH2:26][CH2:25][CH2:24][C:23]([NH:22][C@@H:6]([CH2:5][C:4]1[CH:31]=[C:32]([F:34])[CH:33]=[C:2]([F:1])[CH:3]=1)[C@H:7]([OH:21])[CH2:8][NH:9][C:10]1([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][CH3:20])[CH:14]=3)[CH2:11][CH2:12]1)=[O:30])[CH2:42]2.[CH:27]([OH:29])=[O:28]
Reactant: On1nnc2ccccc21
Reactant: CCc1cccc(C2(NC[C@@H](O)[C@H](Cc3cc(F)cc(F)c3)NC(=O)CCCC(=O)O)CC2)c1
Reactant: ClCCCl
Solvent: CN(C)C=O
Product: CCc1cccc(C2(NC[C@@H](O)[C@H](Cc3cc(F)cc(F)c3)NC(=O)CCCC(=O)N[C@H]3CN4CCC3CC4)CC2)c1
Product: O=CO
Temperature: 45 °C
Reaction time: 8 h
Yield: 49.1 %

Procedure:
To a solution of S-aminoquinuclidine (0.084 g, 0.421 mmol) TEA (0.294 ml, 2.11 mmol), and anhydrous DMF (2.5 ml) was added 5-[((1S,2R)-1-(3,5-difluorobenzyl)-3-{[1-(3-ethylphenyl)cyclopropyl]amino}-2-hydroxypropyl)amino]-5-oxopentanoic acid (0.200 g, 0.421 mmol), EDC (0.121 g, 0.632 mmol), HOBT (0.085 g, 0.632 mmol) under nitrogen, with stirring at 45° C. overnight. Reaction mixture was quenched with 10% sodium bicarbonate (aq.) then extracted with ethyl acetate then concentrated in vacuo, yielding product (0.065 g). Prep-HPLC yielded the product as its formate salt. (ES+: 583.3)
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][CH:13]1[CH2:18][CH2:17][CH:16]([CH2:19][C:20]#[N:21])[CH2:15][CH2:14]1.C(N(CC)CC)C.[Na+].[Cl-]>ClCCl>[CH:12]([CH:13]1[CH2:18][CH2:17][CH:16]([CH2:19][C:20]#[N:21])[CH2:15][CH2:14]1)=[O:11]
Reactant: N#CCC1CCC(CO)CC1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: N#CCC1CCC(C=O)CC1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 80.9 %

Procedure:
To a stirred solution of oxalyl chloride (0.24 mL, 0.0028 mol) in dichloromethane (15 mL) at −78° C. was added a solution of dimethyl sulfoxide (0.23 mL, 0.0032 mol) in dichloromethane (5 mL). After 10 min. a solution of [4-(hydroxymethyl)cyclohexyl]acetonitrile (0.38 g, 0.0025 mol) in dichloromethane (2 mL) was added to the reaction mixture. After 25 min., the reaction mixture was treated with triethylamine (1.7 mL, 0.012 mol), allowed to warm to room temperature, and then poured into 100 mL of saturated aqueous NaCl. The resulting mixture was extracted with two 100 mL portions of ether, dried (MgSO4), and then evaporated under reduced pressure. Chromatography of the residue on silica gel with 1:10 ethyl acetate/hexanes afforded 0.306 g of the desired product. 1H NMR (300 MHz, CDCl3): δ 9.64 (s, 1H), 2.35 (d, 2H J=10.8 Hz) 1.10-2.4 (m, 10H) (major isomer).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[CH:10]=[C:9]([NH2:12])[N:8]=[CH:7][C:6]=2[CH:5]=[CH:4]1)[CH3:2].[CH2:13]=[C:14]([C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1)[CH3:15].[H-].[Na+]>N1C=CC=CC=1>[CH2:1]([N:3]1[C:11]2[CH:10]=[C:9]([NH:12][C:20](=[O:21])[C:19]3[CH:23]=[CH:24][C:16]([C:14]([CH3:15])=[CH2:13])=[CH:17][CH:18]=3)[N:8]=[CH:7][C:6]=2[CH:5]=[CH:4]1)[CH3:2]
Reactant: C=C(C)c1ccc(C(=O)Cl)cc1
Reactant: CCn1ccc2cnc(N)cc21
Agent: [H-]
Agent: [Na+]
Solvent: c1ccncc1
Product: C=C(C)c1ccc(C(=O)Nc2cc3c(ccn3CC)cn2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81 %

Procedure:
In a 50 mL pear flask were added 1-ethyl-1H-pyrrolo[3,2-c]pyridin-6-amine, TFA (1I, 5.2 g, 19 mmol) in pyridine (200 ml). At 0° C., 4-(prop-1-en-2-yl)benzoyl chloride (3.8 g, 21 mmol) was added. After 15 minutes, sodium hydride (0.53 g, 13 mmol) was added, and the reaction was stirred at room temperature for four hours. At 0° C., an additional 0.55 equivalent of 4-(prop-1-en-2-yl)benzoyl chloride was added and the reaction mixture was let stirred for another 15 hours at room temperature. The reaction was quenched by adding saturated NaHCO3 at 0° C. and stirred for 30 minutes. Volatiles were removed in vacuo, and the residue was extracted with ethyl acetate twice. Combined organic layers were dried over MgSO4, filtered and concentrated. The crude mixture was then purified by normal phase column chromatography (SiO2, eluting 20-50% EtOAc) to give the desired product N-(1-ethyl-1H-pyrrolo[3,2-c]pyridin-6-yl)-4-(prop-1-en-2-yl)benzamide (5A, 4.7 g, 15 mmol, 81% yield). 1H NMR (DMSO-d6) δ: 10.61 (s, 4H), 8.64 (s, 4H), 8.32 (s, 4H), 8.04-8.10 (m, 9H), 7.62-7.67 (m, 9H), 7.47 (d, J=3.3 Hz, 4H), 6.57 (dd, J=3.2, 0.9 Hz, 5H), 5.58 (s, 4H), 5.23 (t, J=1.4 Hz, 4H), 4.21 (q, J=7.2 Hz, 9H), 2.16 (d, J=0.5 Hz, 13H), 1.39 (t, J=7.2 Hz, 3H); m.p. 125-8° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[NH2:35][CH2:36][CH2:37][NH:38][C:39]1[N:47]=[C:46]([Cl:48])[N:45]=[C:44]2[C:40]=1[N:41]=[CH:42][N:43]2[CH:49]1[CH2:53][CH2:52][CH2:51][CH2:50]1>ClCCl.O>[Cl:48][C:46]1[N:45]=[C:44]2[C:40]([N:41]=[CH:42][N:43]2[CH:49]2[CH2:53][CH2:52][CH2:51][CH2:50]2)=[C:39]([NH:38][CH2:37][CH2:36][NH:35][C:7](=[O:9])[C:6]2[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:11][CH:10]=2)[N:47]=1
Reactant: NCCNc1nc(Cl)nc2c1ncn2C1CCCC1
Reactant: CSc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CSc1ccc(C(=O)NCCNc2nc(Cl)nc3c2ncn3C2CCCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
200 mg of 4-(methylthio) benzoic acid, 205 mg of 1-hydroxybenzotriazole hydrate, 290 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in 4 ml of dichloromethane are mixed together, 280 mg of the product obtained in Stage 1 of Example 7 is added and the reaction medium is agitated for 4 hours and 30 minutes at ambient temperature. Water is added, followed by separating, washing with ether, drying and 336 mg of expected product is collected.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([C:7]([C:9]([C:11]2[N:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=O)=O)[N:4]=[CH:3][CH:2]=1.[CH3:17][C:18]1[CH:30]=[CH:29][C:21]2[N:22]=[C:23]([NH:25][C:26]([NH2:28])=[NH:27])[NH:24][C:20]=2[CH:19]=1.[OH-].[Na+]>CO.O>[CH3:17][C:18]1[CH:30]=[CH:29][C:21]2[N:22]=[C:23]([N:25]=[C:26]3[NH:28][C:7]4([C:5]5[CH:6]=[CH:1][CH:2]=[CH:3][N:4]=5)[NH:28][C:26](=[N:25][C:23]5[NH:24][C:20]6[CH:19]=[C:18]([CH3:17])[CH:30]=[CH:29][C:21]=6[N:22]=5)[NH:27][C:9]4([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][N:16]=4)[NH:27]3)[NH:24][C:20]=2[CH:19]=1
Reactant: Cc1ccc2nc(NC(=N)N)[nH]c2c1
Reactant: O=C(C(=O)c1ccccn1)c1ccccn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccc2nc(N=C3NC4(c5ccccn5)NC(=Nc5nc6ccc(C)cc6[nH]5)NC4(c4ccccn4)N3)[nH]c2c1

Procedure:
Following the procedure of Example 1, 2,2'-pyridil (603 mg, 2.84 mmol) and 5-methyl-2-guanidinobenzimidazole (489 mg, 2.58 mmol) in methanol (17 mL) was treated with a solution of sodium hydroxide (113.6 mg, 2.84 mmol) in 2.8 mL of water. The title compound was isolated as a grey powder (450 mg, 63% yield). mp: 290-291 ° C. (dec); 1H NMR (300 MHz, d6 -DMSO) δ 11.3 br s, NH, 2 H), 10.0 (br s, NH, 2 H), 8.5 (br s, NH, 2 H), 8.32 (d, J=4.2 Hz, 2 H), 7.54 (t, J=7.6 Hz, 2 H), 7.31 (d, J=7.6 Hz, 2 H), 7.16 (d, J=7.8 Hz, 2 H), 7.16-7.09 (m, 2 H), 7.09 (s, 2 H), 7.14 br s, 2 H), 6.86 (d, J=7.8, Hz, 2 H), 2.34 (s, 6 H); MS (ESI) m/z 555 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[O:5][CH:6]=1.C([Li])CCC.CN(C)[CH:23]=[O:24].[Cl-].[NH4+]>O1CCCC1.CCCCCC.O>[Si:9]([O:8][CH2:7][C:4]1[O:5][CH:6]=[C:2]([CH:23]=[O:24])[CH:3]=1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: CN(C)C=O
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(Br)co1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCc1cc(C=O)co1
Yield: 55 %

Procedure:
To a solution of [(4-bromo-2-furyl)methoxy](t-butyl)dimethylsilane (7.3 g, 25 mmol) that was obtained in Example 1 (1a) in tetrahydrofuran (50 ml) was slowly added dropwise n-butyllithium (a 1.6 M solution in hexane, 17 ml, 28 mmol) at −78° C. with stirring, and the resulting mixture was stirred for 5 minutes. Subsequently, to the reaction mixture was furthermore added N,N-dimethylformamide (3.8 ml, 50 mmol) at the same temperature with stirring, and the resulting mixture was stirred for 45 minutes. After stirring, a saturated aqueous solution of ammonium chloride (10 ml) was added to the reaction mixture to quench the reaction, and the resulting mixture was poured into water (100 ml) and extracted with ether. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo, and the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:49 to 1:19) as the eluent to afford the title compound (3.3 g) in a yield of 55% as a colourless oily product.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=2)[CH2:13]1)[CH3:2].[OH-].[Na+].[C:26]1([CH2:32][C:33](Cl)=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>ClCCl>[CH2:1]([N:3]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=2)[CH2:13]1)[C:33](=[O:34])[CH2:32][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:2]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CCNc1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CCN(C(=O)Cc1ccccc1)c1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine (100 mg) in dichloromethane (3 ml) were sequentially added an aqueous solution of 1N sodium hydroxide (1 ml) and phenylacetyl chloride (0.06 ml) on an ice bath, and the solution was stirred overnight while warming to room temperature. To the reaction solution was added water, the solution was extracted with ethyl acetate, then washed with brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo to provide the title compound (140 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([F:23])[CH:17]=1.C(N(CC)CC)C.[Cl:31]C(Cl)(O[C:35](=[O:41])OC(Cl)(Cl)Cl)Cl.[NH2:43][C:44]1[S:45][CH:46]=[CH:47][N:48]=1>C(Cl)(Cl)Cl.O>[ClH:31].[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:35]([NH:43][C:44]2[S:45][CH:46]=[CH:47][N:48]=2)=[O:41])=[C:18]([F:23])[CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Reactant: Nc1nccs1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4nccs4)c(F)c3)c2cc1OC
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.2 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (12 g) was dissolved in chloroform (350 ml) and triethylamine (50 ml) to prepare a solution. A solution of triphosgene (12 g) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 30 min. Next, 2-aminothiazole (4.77 g) was added thereto, and the mixture was further stirred at room temperature overnight. Iced water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with water and saturated brine and was then dried over anhydrous magnesium sulfate. The dried organic layer was filtered and was then concentrated, and ether was added to the residue for crystallization, followed by collection of the resultant crystal by filtration. The crystal was further washed with methanol and was collected by filtration. A 10% hydrogen chloride-methanol solution was added to the collected crystal, and the solution was concentrated. The resultant crystal was washed with a mixed solution composed of ether and ethanol to give 11.5 g of the title compound.
Reaction SMILES: C(N(CC)CC)C.[CH:8]1([NH2:14])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.Cl[S:16]([C:19]1[CH:28]=[CH:27][C:26]2[NH:25][C:24](=[O:29])[C:23]3[NH:30][CH:31]=[C:32]([C:33]([OH:35])=[O:34])[C:22]=3[C:21]=2[CH:20]=1)(=[O:18])=[O:17]>ClCCl.CN(C)C=O>[CH:8]1([NH:14][S:16]([C:19]2[CH:28]=[CH:27][C:26]3[NH:25][C:24](=[O:29])[C:23]4[NH:30][CH:31]=[C:32]([C:33]([OH:35])=[O:34])[C:22]=4[C:21]=3[CH:20]=2)(=[O:18])=[O:17])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: NC1CCCCC1
Reactant: O=C(O)c1c[nH]c2c(=O)[nH]c3ccc(S(=O)(=O)Cl)cc3c12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)c1c[nH]c2c(=O)[nH]c3ccc(S(=O)(=O)NC4CCCCC4)cc3c12
Temperature: 25 °C
Reaction time: 48 h
Yield: 44.2 %

Procedure:
314 μL (2.25 mmol) of triethylamine and 189 μL (1.65 mmol) of cyclohexylamine are added to 490 mg (1.5 mmol) of 8-chlorosulfonyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid suspended in 4 mL of anhydrous dichloromethane and 1 mL of anhydrous dimethylformamide. The reaction mixture is stirred for 2 days at room temperature. The solvents are evaporated, and the residue is taken up in water. The solid is filtered, rinsed with water then diisopropyl ether and dried under vacuum to give 258 mg (44%) of 8-cyclohexylsulfamoyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid in the form of a cream-coloured solid.
Reaction SMILES: [C:1]([Cl:4])(=[O:3])[CH3:2].[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][CH2:13][N:14]([CH3:32])[CH2:15][CH2:16][CH2:17][CH2:18][C:19]([C:21]1[CH:31]=[CH:30][C:24]2[CH2:25][CH2:26][NH:27][CH2:28][CH2:29][C:23]=2[CH:22]=1)=[O:20].C(N(CC)CC)C.O>O1CCCC1>[ClH:4].[C:1]([N:27]1[CH2:26][CH2:25][C:24]2[CH:30]=[CH:31][C:21]([C:19](=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][N:14]([CH2:13][CH2:12][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[Cl:5])[CH3:32])=[CH:22][C:23]=2[CH2:29][CH2:28]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CN(CCCCC(=O)c1ccc2c(c1)CCNCC2)CCc1ccccc1Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)N1CCc2ccc(C(=O)CCCCN(C)CCc3ccccc3Cl)cc2CC1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Acetyl chloride (54 μl) was added to a solution of 5-[[2-(2-chlorophenyl)ethyl](methyl)amino]-1-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-1-pentanone (294 mg) obtained in Example 205 and triethylamine (13911) in tetrahydrofuran (2 ml). After stirring at room temperature for 60 minutes, water (10 g) was added, extracted with ethyl acetate, and washed with brine. The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and purified by silica gel column chromatography to give a free base compound of the title compound as a pale yellow oil (280 mg). A solution of the free base compound in ethanol was treated with hydrogen chloride (ethyl acetate solution) to give the title compound as pale yellow amorphous powders (220 mg).
Reaction SMILES: [C:1]([O:12][CH2:13][CH2:14][CH2:15]C)(=[O:11])/[CH:2]=[CH:3]\[C:4](OCCCC)=[O:5].[H][H]>[Cr]([O-])([O-])=O.[Cu+2].O>[CH2:1]([OH:11])[CH2:2][CH2:3][CH2:4][OH:5].[C:1]1(=[O:11])[O:12][CH2:13][CH2:14][CH2:15]1
Reactant: CCCCOC(=O)/C=C\C(=O)OCCCC
Reactant: [H][H]
Agent: O=[Cr]([O-])[O-]
Agent: [Cu+2]
Solvent: O
Product: O=C1CCCO1
Product: OCCCCO
Temperature: 250 °C
Reaction time: 0.12 h

Procedure:
Into a 1 liter magnedrive stirred autoclave was placed 200 g. of dibutyl maleate (reagent grade, Matheson Coleman and Bell) and 30 g. of copper chromite hydrogenation catalyst (Calsicat PC 108-80, Mallinckrodt Chemical Works). The autoclave was charged and pressured to 2,900 psig with hydrogen. Heat was then applied and the temperature was slowly brought to approximately 100° C. at which point an exothermic reaction ensued at a temperature increase to 250° C. Cooling water was passed through the internal coils of the autoclave to control the temperature and not to permit it to exceed about 250° C. After about 5 to 10 minutes the internal temperature had returned to approximately 120° C. and the contents of the autoclave were again heated to a temperature of 200° C. and maintained at this temperature and a hydrogen partial pressure of 2,900 psig for a period of 2.5 hours at which time the reaction appeared to be complete. The contents of the autoclave were then cooled and the hydrogen partial pressure was vented to the atmosphere. The catalyst was separated from the liquid autoclave contents by filtration and the filter was washed with n-butanol. Distillation of the filtrate yielded 1,4-butanediol containing a trace of γ-butyrolactone. Analysis of the filtrate by gas-liquid partition chromatographic techniques indicated that 99% of the dibutyl maleate had been converted to products and that the selectivity to 1,4-butanediol was 90%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:29]=[N:28][NH:27][C:5]2=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[N:13]([C:19]3[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][N:20]=3)[N:14]=[C:15]([O:17][CH3:18])[CH:16]=1)[O:8][C:7]2=[O:26].[CH3:30][C:31]1([NH2:35])[CH2:34][S:33][CH2:32]1>CN(C)C=O>[CH3:30][C:31]1([NH:35][C:7]([C:6]2[C:11]([NH:10][C:9]([C:12]3[N:13]([C:19]4[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][N:20]=4)[N:14]=[C:15]([O:17][CH3:18])[CH:16]=3)=[O:8])=[C:2]([Cl:1])[CH:3]=[C:4]3[C:5]=2[NH:27][N:28]=[CH:29]3)=[O:26])[CH2:34][S:33][CH2:32]1
Reactant: CC1(N)CSC1
Reactant: COc1cc(-c2nc3c(Cl)cc4cn[nH]c4c3c(=O)o2)n(-c2ncccc2Cl)n1
Solvent: CN(C)C=O
Product: COc1cc(C(=O)Nc2c(Cl)cc3cn[nH]c3c2C(=O)NC2(C)CSC2)n(-c2ncccc2Cl)n1
Temperature: 60 °C
Reaction time: 72 h
Yield: 44.7 %

Procedure:
To a solution of 500 mg (1.16 mmol) of the above 5-chloro-7-[2-(3-chloro-pyridin-2-yl)-5-methoxy-2H-pyrazol-3-yl]-1H-8-oxa-1,2,6-triaza-cyclopenta[a]naphthalen-9-one in 10 mL of N,N-dimethylformamide is added 396 mg (3.49 mmol) of 3-methyl-thietan-3-ylamine. The reaction is stirred at 60° C. for 72 hours and then concentrated in vacuo. The residue is taken-up with water and ethyl acetate. The phases are separated and the aqueous layer is washed three times with ethyl acetate. The combined organic layers are washed with brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography (SiO2, hexanes/ethyl acetate 1:2) affords 276 mg (44%) of the product as a white solid; LC/MS:532/534 (M+H)+, m.p.: 162-165° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[C:9]([NH:17]CC4C=CC(OC)=CC=4)=[N:10][CH:11]=[C:12]([C:15]#[N:16])[C:13]=3[S:14][C:4]=2[CH:3]=1.O.[O-:28]P([O-])([O-])=O.[K+].[K+].[K+]>OS(O)(=O)=O>[NH2:17][C:9]1[C:8]2[C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=3[S:14][C:13]=2[C:12]([C:15]([NH2:16])=[O:28])=[CH:11][N:10]=1
Reactant: O=P([O-])([O-])[O-]
Reactant: COc1ccc(CNc2ncc(C#N)c3sc4cc(Br)ccc4c23)cc1
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: NC(=O)c1cnc(N)c2c1sc1cc(Br)ccc12

Procedure:
A solution of 7-bromo-1-[(4-methoxybenzyl)amino][1]benzothieno[3,2-c]pyridine-4-carbonitrile in conc. H2SO4 (0.04 M) was stirred at room temperature for 2 h. The mixture was poured into H2O, neutralized with K3PO4, filtered, washed with H2O and dried. The crude product was swished with MeOH to give the title compound.